The major aims of this project have been accomplished through establishment of a large community based family study of adult probands who participate in comprehensive clinical and biologic assessments followed by comparable evaluations of their adult and child relatives. Recruitment of probands and evaluation of relatives are now near completion and analyses of the findings are underway. To date, we have enrolled 343 participants into the study from the community, and 236 from clinical sources. Our total enrollment from all sources is 775 probands, of which almost 500 have completed the study, and 1,231 relatives, including 175 children. Over the past year, 12 probands and 230 relatives have been recruited. Probands represent a range of disorders including: 23% with bipolar, 44% with depression, 55% with anxiety, 52% with migraine, and 17% without any of these conditions. During the next 3 months we plan to complete recruitment of probands and evaluation of relatives and will commence data analysis. In order to identify the core features of mood and anxiety disorders and their overlap with cardiovascular diseases and migraine, we have established a set of clinical, psychophysiological and neuropsychological measures. The comprehensive set of measures in the study are divided into three components: (1) clinical information that includes a semi-structured diagnostic interview for mood and anxiety disorders, structured diagnostic interviews for major headache syndromes and for sleep disorders, family history of psychiatric disorders, sleep disorders and headache syndromes, and a series of self-reported measures of symptoms, sleep patterns and personality, medical history, family structure, history and function, and major life and family events;(2) in person evaluation at the NIH Clinical Center that includes physical and neurological examination;autonomic nervous system evaluation using tilt and valsalva maneuver; laboratory measures of metabolic, cardiovascular, and immunologic function;psychophysiologic evaluation including startle reflex and eyeblink reflex;structural magnetic resonance imaging; and a computerized cognitive assessment battery;and olfactory function;and (3) two-week assessment of daily activities including an electronic diary that assesses daily rhythms including mood, anxiety, sleep, stress, activity, diet, and social activities;heart rate reactivity using a holter monitor;activity and sleep using an actiwatch;and saliva hormones collected four times per day. In the past year, we have been running preliminary analyses on several of these clinical components and working with external collaborators to design and implement analyses of all of the measures in the study. In preparation for the family study analyses, we are now completing the best estimate diagnoses of all available clinical information including the diagnostic interviews and family history reports. The family history reports are providing important information that is leading to diagnostic changes from the direct interview of many of the probands. The familial aggregation and co-aggregation analyses will commence as soon as the best estimate diagnoses are completed. In preparation for these analyses, we have recently combined the data from the Yale Family Study that was completed several years ago with data from our collaborators study in Lausanne, Switzerland. We found a 3- fold increase in migraine among relatives of probands with migraine;significant associations between migraine with social phobia, mania, depression and panic within individuals;and an increased prevalence of migraine among relatives of probands with mood disorders after controlling for migraine and comorbid anxiety. This suggests that there may be common underlying diathesis between mood disorders and migraine. Other methodological projects that are underway that will inform the familial aggregation analyses are assessment of the validity of clinical ratings and the structured diagnostic interview for headache syndromes;systematic assessment of the validity of the NIMH Family Study Diagnostic Interview for Affective Spectrum Disorders compared to the Structure Clinical Interview for DSM-IV (SCID);and validity of the NIMH Sleep Diagnostic Interview compared with sleep disorder diagnoses made by sleep experts. During the past several months, we have begun to examine the non-clinical measures as well, with substantial progress in analysis of the eyeblink reflex, actigraphy, olfactory measures and attention using the Attention Network Test. We have also conducted extensive analyses of links between cardiovascular disease and risk factors, migraine and depression in other data sets to develop specific hypotheses for the analyses of the family study data. Some intriguing findings that have emerged include: greater reactivity of the eyeblink reflex among those with migraine with aura compared to those without aura and non-headache controls;greater variability in activity among those with major depression;and increased orienting to cues in those with migraine with aura, and decreased speed of attention among those with depression. Phase IV: High Risk Study of Offspring Major progress has been achieved during the past year in developing the high risk component of our research. During the past year, we recruited 23 youth, and interviewed 32 of their relatives. The two sources of recruitment include offspring under age 18 of parents already enrolled in our family study, as well as collaboration with the Department of Neurology at the National Childrens Medical Center where we recruit children seeking treatment for headache, and a comparable sample of children from pediatric practices. Initial analyses indicate good to excellent inter-rater reliability of our child diagnostic interview. We are conducting parallel studies of children in the same domains as the adult probands including clinical, psychiatric, physical, neurocognitive, perception, and genetic evaluations. The purpose of the high risk study is to target and recruit offspring of parents with mood spectrum disorders in order to better identify and characterize early signs and symptoms of clinical conditions. Enhancing current understanding of the initial biological and psychological signs of clinical disorder will enable more timely and effective identification and treatment of children at risk. Public Health Impact: Overall, the combination of these clinical, neuropsychological and psychophysiological measures within families will allow us an in-depth analysis of the biological mechanisms crucial for migraine and mood and anxiety disorders and the common diathesis underlying these domains. This will not only lead to a better understanding of these conditions, and assist in identifying common genetic mechanisms, but may also lead to the development of novel treatment options and possible strategies for prevention and early intervention in those with elevated risk for these conditions. Future Plans: During the next year, we plan to complete recruitment of the probands in the subgroups that are too small for meaningful analysis;complete evaluation of relatives of probands enrolled in the protocol during the past year;finish methodologic studies of diagnostic interviews developed in the study;and complete initial analyses of familial aggregation and co-aggregation, and of the biomarkers and endophenotypes included in the study. Once such analyses are completed, we will plan for future follow-up or extension of selected subgroups in the sample.